Xanthine derivatives

ABSTRACT

Novel xanthine compounds represented by the following formula: ##STR1## wherein each of X 1  and X 2  independently represents oxygen or sulfur; and Q represents; ##STR2## where ----- represents a single bond or a double bond; Y represents a single bond or alkylene, n represents 0 or 1, each of W 1  and W 2  independently represents hydrogen, lower alkyl or amino, Z represents --CH 2  -, --O--, --S-- or --NH--; represents ##STR3## each of R 1  and R 2  independently represents hydrogen, lower alkyl, allyl or propargyl; and R 3  represents hydrogen or lower alkyl, and when Q represents the groups other than ##STR4## each of R 1 , R 2  and R 3  independently represents hydrogen or lower alkyl; 
     provided that when Q is ##STR5## then R 1  R 2  and R 3  are not 
     simultaneously methyl; and pharmaceutically acceptable salts thereof have a diuretic effect, a renal-protecting effect and a bronchodilatory effect.

This application is a continuation-in-part of application Ser. No.574,447, filed Aug. 29, 1990, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel xanthine compounds having adiuretic effect, a renal-protecting effect and a bronchodilatory effect.

Heretofore, theophylline, i.e., 1,3-dimethylxanthine has been known as adiuretic, a vasodilator, etc. [The Merck Index, 10th edition, 9110(1983)].

Xanthine compounds carrying, at the 8-position thereof, substituentssuch as alkyl, alicyclic alkyl, aralkyl, aryl, etc. have a diureticeffect, as disclosed in East German Patent No. 31,772 [Chem. Abst., 63,18120d (1965)]and West German Patent No. 1,245,969 [Chem. Abst., 67,90994n (1967)].

In relation to the compounds of the present invention,8-(1-adamantyl)-1,3,7-trimethylxanthine is described in TetrahedronLett., 27, 6337 (1986). However, nothing is mentioned on itspharmacological effect. Further, 8-(1-adamantyl)-1,3-dipropylxanthinehaving an activity of antagonizing adenosine A₁ receptor is described inJ. Med. Chem., 33, 1906 (1990).

The object of the present invention is to provide novel xanthinecompounds exhibiting strong diuretic and renal-protecting effect, basedon the finding that xanthine compounds which are adenosine receptorantagonists, particularly those having an activity of selectivelyantagonizing adenosine Al receptor, have strong diuretic andrenal-protecting effect.

SUMMARY OF THE INVENTION

The present invention relates to a xanthine compound represented by thefollowing formula (I): ##STR6## wherein each of X¹ and X² independentlyrepresents oxygen or sulfur; and Q represents: ##STR7## where -----represents a single bond or a double bond; Y represents a single bond oralkylene, n represents 0 or 1, each of W¹ and W² independentlyrepresents hydrogen, lower alkyl or amino, Z represents --CH₂ --, --O--,--S' or --NH--; such that when Q represents ##STR8## each of R¹ and R²independently represents hydrogen, lower alkyl, allyl or propargyl, andR³ represents hydrogen or lower alkyl, and when Q represents groupsother than ##STR9## each of R¹, R² and R³ independently representshydrogen or lower alkyl;

provided that when Q is ##STR10## then R¹, R² and R³ are not

simultaneously methyl; referred to as "Compound (I)" and compounds withother formula numbers are likewise referred to], or a pharmaceuticallyacceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

In the definition of the respective groups in the formula (I), the loweralkyl includes straight or branched alkyl having 1 to 6 carbon atoms,for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, etc The alkyleneincludes straight or branched alkylene having 1 to 4 carbon atoms, forexample, methylene, ethylene, trimethylene, tetramethylene,methylmethylene, propyplene, ethylethylene, etc.

The pharmaceutically acceptable salt of Compound (I) includespharmaceutically acceptable acid addition salt, metal salt, ammoniumsalt, organic amine addition salt, amino acid addition salt, etc.

The pharmaceutically acceptable acid addition salt of Compound (I)includes inorganic acid salt such as hydrochloride, sulfate, phosphate,etc., and organic acid salt such as acetate, maleate, fumarate, oxalate,citrate, etc.

The pharmaceutically acceptable metal salt includes alkali metal saltsuch as sodium salt, potassium salt, etc., alkaline earth metal saltsuch as magnesium salt, calcium salt, etc., and also aluminum and zincsalts.

The pharmaceutically acceptable ammonium salt includes salts ofammonium, tetramethylammonium, etc. The pharmaceutically acceptableorganic amine addition salt includes addition salts of morpholine,piperidine, etc., and the pharmaceutically acceptable amino acidaddition salt includes addition salts of lysine, glycine, phenylalanine,etc.

A process for producing Compound (I) of the present invention isdescribed below.

Compound (I-1) which is Compound (I) wherein R³ is hydrogen, is producedby the following production steps: ##STR11## wherein Hal representshalogen such as chlorine, bromine or iodine and R¹, R², X¹, X² and Qhave the same meanings as defined above.

Step 1

A Compound (IV) can be obtained by reacting a uracil derivative (II)obtained according to a well known process [for example, the processdisclosed in Japanese Published Unexamined Patent Application No.42383/84] with carboxylic acid (III) or a carboxylic acid reactivederivative.

The carboxylic acid reactive derivative includes acid halides such asacid chlorides, acid bromides, etc., active esters such as p-nitrophenylester, N-oxysuccinimide ester, etc., acid anhydrides commerciallyavailable or those formed from carbodiimides such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, diisopropylcarbodiimide,dicyclohexylcarbodiimide, etc.; mixed acid anhydrides with monoethylcarbonate, monoisobutyl carbonate, etc. and so forth.

The reaction of Compound (II) with Compound (III) is carried out withoutany solvent at a temperature of 50° to 200° C. In the case of using thecarboxylic acid reactive derivative, the reaction can be carried outaccording to a process usually used in the peptide chemistry. Forexample, the reaction solvent is properly selected fromhalogenohydrocarbons such as methylene chloride, chloroform,dichloroethane, etc., ethers such as dioxane, tetrahydrofuran, etc.,dimethylformamide and dimethylsulfoxide, and if necessary water is used.The reaction temperature is -80° to 50° C., and the reaction iscompleted for 0.5 to 24 hours. Sometimes, the reaction may be favorablycarried out, if necessary, in the presence of an additive such as1-hydroxybenzotriazole, etc., or a base such as pyridine, triethylamine,dimethylaminopyridine, N-methylmorpholine, etc. Furthermore, thecarboxylic acid reactive derivative may be formed in the reaction systemand used without isolation.

Step 2

A desired Compound (I-1) is obtained from Compound (IV) by the reactionin the presence of a base (process A), by treatment with a dehydratingagent (process B), or by heating (process C).

As the preferable base in the process A, alkali metal hydroxides such assodium hydroxide, potassium hydroxide, etc. can be exemplified. As thereaction solvent, water, lower alcohols such as methanol, ethanol, etc.,ethers such as dioxane, tetrahydrofuran, etc., dimethylformamide,dimethylsulfoxide, etc. can be used alone or in combination. Thereaction is carried out at a temperature of from room temperature to180° C. and is usually completed for 10 minutes to 6 hours.

As the dehydrating agent for use in the process B, thionyl halides suchas thionyl chloride, etc., and phosphorus oxyhalides such as phosphorusoxychloride, etc. can be used, and the reaction is carried out at atemperature of from room temperature to 180° C. without any solvent orin a solvent inert to the reaction, for example, halogenohydrocarbonssuch as methylene chloride, chloroform, dichloroethane, etc.,dimethylformamide, dimethylsulfoxide, etc. and is usually completed for0.5 to 12 hours.

In the case of process C, the Compound (I-1) can be obtained by heatingCompound (IV) at a temperature of 50° to 200° C. in a polar solvent suchas dimethylsulfoxide, dimethylformamide Dowthermo A (product ofMuromachi Kagaku Kogyo Kaisha, Ltd.), etc.

Step 3

A schiff base (VI) can be obtained by reacting Compound (II) withaldehyde (V) in a mixed solvent such as a mixture of acetic acid with alower alcohol such as methanol, ethnnol, etc. at a temperature of -20°to 100° C.

Step 4

A desired Compound (I-1) can be obtained by subjecting Compound (VI) toan oxidative cyclization reaction.

As the appropriate oxidizing agent, oxygen, ferric chloride, ceriumIVammonium nitrate, diethyl azodicarboxylate, etc. can be exemplified. Thereaction is carried out by heating Compound (VI) at from roomtemperature to 180° C. in the presence of the afore-mentioned oxidizingagent and, if necessary, in a solvent inert to the reaction, forexample, a lower alcohol such as methanol, ethanol, etc., ahalogenohydrocarbon such as methylene chloride, chloroform, etc., or anaromatic hydrocarbon such as toluene, xylene, nitrobenzene, etc.

Step 5

A Compound (IX) can be obtained by reacting a uracil derivative (VII)obtained according to a well known process, for example, the processdescribed in Japanese Published Unexamined Patent Application No.5082/86 with an amine (VIII) in a solvent inert to the reaction, forexample, a lower alcohol such as methanol, ethanol, etc.,dimethylformamide, dimethylsulfoxide, etc. alone or in combinationthereof at a temperature of 50° to 150° C.

Step 6

A Compound (I-1) can be obtained by reacting a Compound (IX) with anitrosating agent such as sodium nitrite, isoamyl nitrite, etc. under anacidic condition with dilute hydrochloric acid, etc. in a solvent inertto the reaction, for example, a lower alcohol such as methanol, ethanol,etc. usually at a temperature of from room temperature to the boilingpoint of the solvent.

Step 7

A Compound (I-2) which is Compound (I) wherein R³ is a lower alkyl groupcan be obtained through the following step: ##STR12## wherein R¹, R²,X¹, X² and Q have the same meanings as defined above, R^(3a) representslower alkyl in the definition of R³.

A desired compound (I-2) can be obtained by reacting Compound (I-1)obtained in Steps 1 to 6 with an alkylating agent preferably in thepresence of a base.

As the alkylating agent, alkyl halides, dialkyl sulfates, diazoalkanes,etc. are used.

As the base, an alkali metal carbonate such as sodium carbonate,potassium carbonate, etc., an alkali metal hydride such as sodiumhydride, etc., and an alkali metal alkoxide such as sodium methoxide,sodium ethoxide, etc. are exemplified. The reaction is completed at atemperature of 0° to 180° C. usually for 0.5 to 24 hours.

Step 8

Compound (I-4) which is Compound (I) wherein X² is sulfur, can beobtained by the following step. ##STR13## wherein R¹, R², R³, X¹ and Qhave the same meanings as previously defined.

A desired Compound (I-4) was prepared by reacting Compound (I-3) whichis Compound (I) wherein X² is oxygen, with an appropriate thionationreagent, in an inert solvent. As the thionation reagent, phosphoruspentasulfide and the like are mentioned. As the solvent,dimethylformamide, tetrahydrofuran, dioxane, etc. are mentioned, andpreferably pyridine and the like are used. The reaction is carried outat a temperature of 50° to 180° C. for a period of 10 minutes to 36hours.

Step 9

Compound (I-5) which is Compound (I) wherein R³ is hydrogen and X² isoxygen, can be obtained by the following step. ##STR14## wherein R¹, R²,X¹ and Q have the same meanings as previously defined.

Compound (I-5) can be obtained by reacting Compound (X) obtainedaccording to a similar procedure to Steps 1 to 6 with an equimolaramount of an alkylating agent, if necessary, in the presence of a base.

As the alkylating agent, alkyl halides such as alkyl bromide, propargylbromide, etc., sulfonic acid esters such as propargylp-toluenesulfonate, allyl methanesulfonate, etc. are used.

As the base, an alkali metal carbonate such as sodium carbonate,potassium carbonate, etc., an alkali metal hydride such as sodiumhydride, etc., and an alkali metal alkoxide such as sodium methoxide,sodium ethoxide, etc. are exemplified. As the reaction solvent, loweralcohols such as methanol, ethanol, etc., ethers such as dioxane,tetrahydrofuran, etc., dimethylformamide, dimethylsulfoxide, etc. can beused alone or in combination. The reaction is carried out at atemperature of from room temperature to 180° C. and usually completed infrom 10 minutes to 6 hours.

The intermediates and the desired compound obtained according to theaforementioned processes can be isolated and purified by subjecting themto a purification process usually used in the organic syntheticchemistry, for example, filtration, extraction, washing, drying,concentration, recrystallization, various chromatographies, etc. Theintermediates can be used in the successive reaction without anypurification.

Salts of Compound (I) can be obtained by direct purification whenCompound (I) can be obtained in a salt form, or by formation of a saltaccording to a usual procedure when the Compound (I) is obtained in afree form, and a subsequent purification.

Compound (I) and its pharmaceutically acceptable salts sometimes existin an adduct form with water or various other solvents, and theseadducts are included in the present invention.

Optical isomers may exist with respect to Compound (I), and all thepossible stereoisomers and their mixtures are also included in the scopeof the present invention.

Specific examples of Compound (I) are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________     ##STR15##                                                                    Compound No.                                                                  (Example No.)                                                                         R.sup.1    R.sup.2  R.sup.3  Q             X.sup.1                                                                          X.sup.2                 __________________________________________________________________________    .sup. 1 (1)                                                                           n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR16##    O  O                       .sup. 2 (1)                                                                           n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR17##    O  O                       .sup. 3 (2)                                                                           n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR18##    O  O                       .sup. 4 (2)                                                                           n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR19##    O  O                       .sup. 5 (3)                                                                           n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR20##    O  O                       .sup. 6 (3)                                                                           n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR21##    O  O                       .sup. 7 (4)                                                                           n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR22##    O  O                       .sup. 8 (5)                                                                           n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR23##    O  O                       .sup. 9 (6)                                                                           n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR24##    O  O                        .sup. 10 (7)                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR25##    O  O                       .sup. 11 (8)                                                                          n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR26##    O  O                       .sup. 12 (9)                                                                          n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR27##    O  O                       .sup. 13 (29)                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR28##    O  O                       .sup. 14 (10)                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR29##    O  O                       .sup. 15 (11)                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR30##    O  O                       .sup. 16 (12)                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR31##    O  O                       .sup. 17 (13)                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      CH.sub.3                                                                                ##STR32##    O  O                       .sup. 18 (14)                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      CH.sub.3                                                                                ##STR33##    O  O                       .sup. 19 (30)                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      CH.sub.3                                                                                ##STR34##    O  O                       .sup. 20 (15)                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      CH.sub.3                                                                                ##STR35##    O  O                       .sup. 21 (16)                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      C.sub.2 H.sub.5                                                                         ##STR36##    O  O                       .sup. 22 (17)                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      n-C.sub.3 H.sub.7                                                                       ##STR37##    O  O                       .sup. 23 (18)                                                                         H          n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR38##    O  O                       .sup. 24 (19)                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR39##    S  O                       .sup. 25 (20)                                                                         H          n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR40##    O  O                       .sup. 26 (21)                                                                         H          n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR41##    O  S                       .sup. 27 (22)                                                                         CH.sub.3   CH.sub.3 H                                                                                       ##STR42##    O  O                       .sup. 28 (23)                                                                         C.sub.2 H.sub.5                                                                          C.sub.2 H.sub.5                                                                        H                                                                                       ##STR43##    O  O                       .sup. 29 (24)                                                                         n-C.sub.4 H.sub.9                                                                        n-C.sub.4 H.sub.9                                                                      H                                                                                       ##STR44##    O  O                       .sup. 30 (25)                                                                         CH.sub.3   iso-C.sub.4 H.sub.9                                                                    H                                                                                       ##STR45##    O  O                       .sup. 31 (26)                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR46##    S  O                       .sup. 32 (27)                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR47##    O  S                       .sup. 33 (28)                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                                                      H                                                                                       ##STR48##    S  S                       .sup. 34 (31)                                                                         CH.sub.2 CHCH.sub.2                                                                      CH.sub.2 CHCH.sub.2                                                                    H                                                                                       ##STR49##    O  O                       .sup. 35 (32)                                                                         CHCCH.sub.2                                                                              CH.sub.2 CHCH.sub.2                                                                    H                                                                                       ##STR50##    O  O                       __________________________________________________________________________

Compound (I) and its pharmaceutically acceptable salts have an activityof selectively antagonizing adenosine

A₁ receptor, and thus exhibit, a diuretic effect, a renal-protectingeffect a bronchodilatory effect, etc. Compound (I) and itspharmaceutically acceptable salts are useful as a diuretic andrenal-protecting agent, bronchodilatory agent, etc.

The pharmacological effects of Compound (I) are explained, referring toTest Examples.

Test Example 1, Acute Toxicity Test

A test compound (300 mg/kg) was orally administered to male dd-strainmice having a body weight of 20±1 g (3 animals/group). Minimum lethaldose (MLD) of the compounds was determined by observing whether or notthe mice were alive after 7 days of the administration.

With respect to Compound Nos. 1--5, 7--11, 13--18, 20 23, 24 and 31--33,the MLD was more than 300 mg/kg, and with respect to Compound No. 12,that was 300 mg/kg. This shows the toxicity of Compound (I) is weak andcan be administered safely over a wide range of dosage.

Test Example 2, Adenosine Receptor Binding Test 1) Adenosine A₁ ReceptorBinding

This test was conducted according to the method of Bruns et al. [Proc.Natl. Acad. Sci., 77, 5547 (1980)] with some modification.

Cerebrum of a guinea pig was suspended into ice cooled 50 mM trishydroxymethyl aminomethane hydrochloride (Tris HCl) buffer (pH=7.7), byusing Polytron homogenizer (manufactured by Kinematica Co.). Thesuspension was centrifuged (50,000×g, 10 minutes), and the precipitatewas resuspended by adding the same volume of 50 mM Tris HCl buffer. Thesuspension was centrifuged under the same conditions, and theprecipitate obtained was suspended once again by adding 10 volumes of 50mM Tris HCl The tissue suspension was incubated at 37° C. for 30 minutesin the presence of 0.02 units/mg tissue of adenosine deaminase(manufactured by Sigma Co.). The resulting tissue suspension wasrecentrifuged (50,000×g, 10 minutes), and 50 mM Tris HCl was added tothe precipitate to adjust the concentration of tissue to 10 mg (wetweight)/ml.

To 1 ml of tissue suspension prepared above were added 50 μl of [³ H]cyclohexyladenosine [³ H-CHA, 27 Ci/mmol, manufactured by New EnglandNuclear Co.] (final concentration =1.1 nM) and 50 μl of test compound.The mixture was incubated at 25° C. for 90 minutes, and the resultingmixture was stopped by rapid vacuum filtration through a glass fiberfilter (GF/C manufactured by Whatman Co.) and immediately washed threetimes with 5 ml each of ice cold 50 mM Tris HCl buffer. The filter wastransferred to a vial bottle, and a scintillator (EX-H by Wako PureChemicals Industries, Ltd.) was added thereto. Its radioactivity wasthen determined by a scintillation counter (manufactured by PackardInstrument Co.).

The inhibition rate of the test compound against the binding of Alacceptor (³ H-CHA binding) was calculated from the following equation:##EQU1##

The results are shown in Table 2. The inhibition constant (Ki value)shown in the table was calculated from Cheng-Prusoff's equation. 2)Adenosine A₂ Acceptor Binding Test

This test was conducted according to the method of Bruns et al. [Mol.Pharmacol., 29, 331 (1986)] with some modification.

A precipitate was prepared from rat corpus striatum in a similar manneras in 1) above. The precipitate was suspended by adding a 50 mM Tris HClbuffer containing 10 mM magnesium chloride and 0.02 unit/mg (tissue) ofadenosine deaminase (manufactured by Sigma Co.) to adjust theconcentration of tissue to 5 mg (wet weight)/ml.

To 1 ml of tissue suspension prepared above were added 50 μl of amixture of N-ethylcarboxamidoadenosine [³ H-NECA, 26 Ci/mmol,manufactured by Amersham Co.] (final concentration=3.8 nM) andcyclopentyladenosine [CPA, manufactured by Sigma Co.] (finalconcentration=50 nM), and 50 μl of test compound. The mixture wasincubated at 25° C. for 120 minutes. The resulting mixture was treatedin the same manner as in 1) above to determine its radioactivity.

The inhibition rate of the test compound against the binding of A2receptor (³ H-NECA binding) was calculated from the following equation:##EQU2##

The results are shown in Table 2. The Ki values shown in the table werecalculated from the following equation: ##EQU3##

                                      TABLE 2                                     __________________________________________________________________________           A.sub.1 Receptor                                                                             A.sub.2 Receptor                                               Inhibition (%)/                                                                              Inhibition (%)/                                                                              Ratio                                           Concentration  Concentration  of Ki                                    Compound                                                                             of Tested Compound                                                                       Ki  of Tested Compound                                                                       Ki  Values                                   No.    [10.sup.-5 /10.sup.-4 M]                                                                 (nM)                                                                              [10.sup.-5 /10.sup.-4 M]                                                                 (nM)                                                                              [A.sub.2 /A.sub.1 ]                      __________________________________________________________________________    1      99/99      5.5 88/97      510 92.7                                     3      100/100    4.4 83/90      330 75.0                                     5      99/99      3.8 91/99      330 86.8                                     6      100/101    5.0 70/85      560 112                                      13     100/100    7.8 63/71      1,400                                                                             179                                      14     101/101    1.3 63/77      380 292                                      28     100/101    7.1 61/78      940 132                                      29     100/100    9.1 72/78      970 107                                      XAC*.sup.1                                                                           98(10.sup.-6 M)                                                                          11  99/--      21  1.91                                     PD 115199*.sup.2                                                                      97/100    190 94/98      26  0.14                                     CGS 15943*.sup.3                                                                     99/96      10  99/97      0.73                                                                              0.073                                    Theophylline                                                                         33/74      23,000                                                                            26/69      20,000                                                                            0.87                                     __________________________________________________________________________     [Notes                                                                        *.sup.1 Xanthineaminecongener                                                 ##STR51##                                                                     [Mol. Pharmacol., 29, 126 (1986)]-                                            ##STR52##                                                                     [NaunynSchmiedeberg's Arch. Pharmacol., 335, 64                               1987)]-                                                                       ##STR53##                                                                     [J. Med. Chem., 31, 1014 (1988)]-                                        

Test Example 3, Diuretic Effect

Wistar rats (male: 150-300 g) were starved for 18 hours prior to theadministration of the test compound. A test compound (25 mg/kg) andsaline (25 ml/kg) were orally administered to test rats and only salinewas administered to control rats. Three groups, each group consisting of3 rats, were used for each test compound. Urine was collected for 6hours after the administration. Urine volume was measured and theelectrolytes (Na⁺ and K⁺) in the urine wee determined with a flamephotometer (775A, Hitachi Ltd., Japan). The results are shown in Table3.

All parameters are expressed as relative values of control.

                  TABLE 3                                                         ______________________________________                                                   Increase Increase in                                                                             Increase in                                     Compound   in Urine Na.sup.+  excre-                                                                        K.sup.+  excre-                                 No.        (%)      tion (%)  tion (%)                                                                              Na.sup.+ /K.sup.+                       ______________________________________                                        (Control)   0        0         0      1.00                                     1         106       73       36      1.27                                     2          87      109       67      1.25                                     3         154      137       29      1.84                                     4         113      106       27      1.63                                     5          88      109       32      1.58                                      6*.sup.3 330      252       87      1.88                                     8          82      138       22      1.95                                    12         108      103       32      1.54                                    13         129      186       37      2.09                                    14         315      244       68      2.05                                    16         141      191       38      2.12                                    17         155      107       51      1.37                                    24         112      125       61      1.40                                    29         123      137       65      1.43                                    30         112      126       50      1.50                                    31         115      126       56      1.44                                    32         100      114       41      1.51                                    33          99      105       40      1.47                                    Aminophylline*.sup.1                                                                      34       89       17      1.62                                    (Reference                                                                    compound)                                                                     Furosemide*.sup.2                                                                         75       64       57      1.07                                    (Reference                                                                    compound)                                                                     ______________________________________                                         *.sup.1 The Merck Index, 10th edition, page 476 (1983)                        *.sup.2 The Merck Index, 10th edition, page 4189 (1983)                       *.sup.3 The amount of the administration: 6.25 mg/kg                     

Test Example 4, Renal-Protecting Effect (Glycerol-Induced Renal FailureModel)

A renal failure is a state where the renal function is lowered and thehomeostasis of a body fluid can be no more maintained. It is known thatan acute renal failure characteristic of uriniferous tubule disorder iscaused by subcutaneous or intramuscular injection of glycerol to rats[Can. J. Physiol. Pharmacol., 65, 42 (1987)].

Male Wistar rats were kept deprived of water for 18 hours, and servedfor the test. A test compound was intraperitoneally administered to therats (dosage: 1 ml/kg) and the rats were anesthetized with ether and 50%glycerol was subcutaneously administered (dosage: 0.8 ml/100 g) to therats, pinching the dorsal skin. Twenty four hours after theadministration of glycerol, the rats were anesthetized with ether and 5ml of blood was collected from the abdominal aorta. The collected bloodwas allowed to stand for 30 minutes or longer and then centrifuged at3,000 rpm for 10 minutes, and the amounts of the serum creatinine andurine-nitrogen (UN) contained in a serum were determined by autoanalyzer (Olympus AU510) or measured by the creatinine test Wako (Jaffemethod) and UN Test Wako (diacetylmonooxime direct method). Both aremanufactured by Wako Pure Chemicals Co.

On the other hand, the left kidneys of the blood-sampled rats wereremoved and placed in formalin-filled vial bottles, and used as samplesfor the pathological examination.

According to the test results, Compound Nos. 1--5, 7, 8, 13, 14, 16, 17,23, 25 and 31 significantly suppressed increases in the serum creatinineand in urine-nitrogen, when administered abdominally at a dosage of0.01 - 10 mg/kg [i.p.] (p <0.05) whereas XAC and aminophylline had aweak effect of suppressing the increase, and PD 115,199 and CGS15,943were totally invalid. On the contrary, furosemide showed a tendency toincrease the serum creatinine. The pathological examination of removedkidneys indicates that compounds Nos. 1 -5, 7, 8, 13, 14, 16, 17, 23, 25and 31 also significantly improved the state of kidneys.

Test Example 5, Effects On Passive Schultz-Dale Reaction

Male Hartley guinea pigs weighing 350 to 500 g were passively sensitizedby intraperitoneal injection of rabbit anti-egg white albumin (EWA)serum prepared by the method of Koda, et al. [Folia pharmacol, Japan 66,237 (1970)]. After 24 h the guinea pigs were stunned and exsanguinated,and then the trachea were removed. The zig-zag strips of the tracheawere prepared by the method of Emmerson, et al. [J. Pharm. Pharmacol.,31, 798 (1979)]. The strips were suspended in Krebs-Henseleit solutionat 37° C. aerated with 95% O₂ and 5% CO₂, and incubated for one hour.Antigen (EWA) was then introduced in the solution (final concentration;1 μg/ml), and the contraction was measured by isotonictransducer(TD-112s, Nihon Kohden, Japan) and recorded on a recorder (Type 3066,Yokogawa-Hokushin Denki, Japan). After the contraction reached a stableplateau, the compounds were cumulatively added in order to getconcentration-relaxation curves. Concentration of compounds to produce50% relaxation (IC₅₀) was calculated from the regression curve, obtainedfrom cumulative concentration-relaxation response. The results are shownin Table 4.

                  TABLE 4                                                         ______________________________________                                                  Passive                                                                       S-D Reaction                                                                              MED (mg/kg) for Inhibiting                              Compound No.                                                                            IC.sub.50 (μM)                                                                         Death Induced by PAF                                    ______________________________________                                         7        2.7         >100                                                     8        0.88        100                                                     25        17.3        --                                                      26        22.7        --                                                      Theophylline                                                                            23          100                                                     ______________________________________                                    

Test Example 6, Effect of Inhibiting Death Induced ByPlatelet-Activating Factor (PAF)

A test compound (100 mg/kg) was orally administered to dd strain mice(male animals, 28 to 32 g) and 40 μg/kg of PAF (manufactured by AvantiPolar Lipids Co.) was administered via tail veins 1 hour after theadministration according to the method of Carlson et al. [Agents andActions, 21, 379 (1987)]. The mortality rates of compound-treated groupswere compared with those of matched control groups, assessed during thesame experimental session, by the Fisher's exact probability test. Thecases wherein the level of significance (p value) is 0.05 or less areconsidered to be effective with respect to the inhibition. The aboveprocedure was repeated, using the test compound in a decreasingly smallquantity so as to find out the Minimum Effective Dosage (MED) wherein nosignificant difference be observed between the test and control groups.

The results are shown in Table 4.

Test Example 7, Acute Toxicity Test

A test compound was orally administered to male dd-strain mice having abody weight of 20±1 g (3 animals/group). Minimum lethal dose (MLD) ofthe compound was determined by observing whether or not the mice werealive after 7 days of the administration.

With respect to Compound 34, the MLD was more than 300 mg/kg. This showsthe toxicity of Compound (I) is weak and can be administered safely overa wide range of dosage.

Test Example 8, Adenosine A₁ Receptor Binding Test

This test was conducted according to the method of Bruns et al. [Proc.Natl. Acad. Sci., 77, 5547 (1980)] with some modification.

Cerebrum of a guinea pig was suspended into ice cooled 50 mM trishydroxymethyl aminomethane hydrochloride (Tris HCl) buffer (PH 7.7), byusing Polytron homogenizer (manufactured by Kinematica Co.). Thesuspension was centrifuged (50,000×g, 10 minutes), and the precipitatewas resuspended by adding the same volume of 50 mM Tris HCl buffer. Thesuspension was centrifuged under the same conditions, and theprecipitate obtained was suspended once again by adding 50 mM Tris HCluntil the concentration of tissue was 100 mg (wet weight)/ml. The tissuesuspension was incubated at 37° C. for 30 minutes in the presence of0.02 units/mg tissue of adenosine deaminase (manufactured by Sigma Co.).The resulting tissue suspension was recentrifuged (50,000×g, 10minutes), and 50 mM Tris HCl was added to the precipitate until theconcentration of tissue was 10 mg (wet weight)/ml.

To 1 ml of tissue suspension prepared above were added 50 μl of [³ H]cyclohexyladenosine [³ H-CHA, 27 Ci/mmol, manufactured by New EnglandNuclear Co. ] (final concentration: 1.1 nM) and 50 μl of the testcompound. The mixture was incubated at 25° C. for 90 minutes, and theresulting mixture was stopped by rapid vacuum filtration through a glassfiber filter (GF/C manufactured by Whatman Co.) and immediately washedthree times with 5 ml each of ice cold 50 mM Tris HCl buffer. The filterwas transferred to a vial bottle, and a scintillator (EX-H by Wako PureChemical Industries, Ltd.) was added thereto. Its radioactivity was thendetermined by a scintillation counter (manufactured by PackardInstrument Co.).

The inhibition rate of the test compound against the binding of A₁receptor (³ H-CHA binding) was calculated from the following equation:

    Inhibition (%)=(1-(([B]-[N])/([T]-[N])))×100

[Notes]

1. "B" means the radioactivity of ³ H-CHA bound in the presence of atest compound at a concentration shown in Table 1.

2. "T" means the radioactivity of ³ H-CHA bound in the absence of a testcompound.

3. "N" means the radioactivity of ³ H-CHA bound in the presence of 10 μMof N⁶ -(L-2-phenylisopropyl)adenosine (manufactured by Sigma Co.).

The results are shown in Table 5. The inhibition constant (Ki value)shown in the table was calculated from Cheng-Prusoff's equation.

                  TABLE 5                                                         ______________________________________                                                     A.sub.1 Receptor                                                                Inhibition (%)/                                                               Concentration of                                                              Test Compound                                                  Compound No.   [10.sup.-5 /10.sup.-4 M]                                                                   Ki (nM)                                           ______________________________________                                        34             99/99        15                                                ______________________________________                                    

According to the result, Compound 34 almost perfectly inhibited against³ H-CHA binding (the binding of A₁ receptor).

Test Example 9, Diuretic Effect

Wistar rats (male: 150-300 g) were starved for 18 hours prior to theadministration of a test compound. The test compound was suspended insaline, and the test compound was orally administered to rats at aconcentration of 0.1 to 10 mg/25 ml/kg. Only saline was administered torats. The rats to which only saline was administered was made as controlgroup. Three groups, each group consisting of 3 rats, were used for eachtest. Urine was collected for 6 hours after the administration. Urinevolume was measured and the electrolytes (Na⁺ and K⁺) in the urine weredetermined with a flame photometer (775A, Hitachi Ltd., Japan). Theresults are shown in Table 6.

All parameters are expressed as relative values of control.

                  TABLE 6                                                         ______________________________________                                                The                                                                           amount                                                                        of the            Increase                                                                             Increase                                             adminis- Increase in Na.sup.+                                                                          in K.sup.+                                   Compound No.                                                                          tration  in Urine excretion                                                                            excretion                                    No.     (mg/kg)  (%)      (%)    (%)    Na.sup.+ /K.sup.+                     ______________________________________                                        (Control)                                                                             --        0        0      0     1.00                                  34      6.25     82       71     18     1.45                                  34      0.40     109      99      8     1.84                                  Amino-  25       34       89     17     1.62                                  phylline*.sup.1                                                               (Reference                                                                    compound)                                                                     Furose- 25       75       64     57     1.07                                  mide*.sup.2                                                                   (Reference                                                                    compound)                                                                     ______________________________________                                         *.sup.1 The Merck Index, 11th edition, page 76 (1989)                         *.sup.2 The Merck Index, 11th edition, page 674 (1989)                   

The result indicates that diuretic effect of Compound 34 is higher thanthat of Aminophylline or Furosemide.

Test Sample 10 Renal-Protecting Effect (Glycerol-Induced Renal FailureModel)

A renal failure is a state where the renal function is lowered and thehomeostasis of a body fluid can no longer be maintained. It is knownthat an acute renal failure characteristic of uriniferous tubuledisorder is caused by subcutaneous or intramuscular injection ofglycerol to rats [Can. J. physiol. pharmacol., 65, 42 (1987)].

Male Wistar rats were kept deprived of water for 18 hours, and servedfor the test. A test compound was intraperitoneally administered to therats (dosage: 0.1 mg/l ml/(saline)/kg) and the rats were anesthetizedwith ether and 50% glycerol was subcutaneously administered (dosage: 0.8mg/100 g) to the rats, pinching the dorsal skin. Twenty four hours afterthe administration of glycerol, the rats were anesthetized with etherand 5 ml of blood was collected from the abdominal aorta. The collectedblood was allowed to stand for 30 minutes or longer and then centrifugedat 3,000 rpm for 10 minutes, and the amounts of the serum creatinine andthe serum urine-nitrogen (UN) were determined by auto analyzer (OlympusAU510) [creatine test (Jaffe method), UN test (enzyme method); bothtests were used in Olympus AU500/550 exclusive reagent] or measured bythe Creatinine Test Wako (Jaffe method) and UN Test Wako(diacetylmonooxime direct method). Both are manufactured by Wako PureChemicals Co.

On the other hand, the left kidneys of the blood-sampled rats wereremoved and placed in formalin-filled vial bottles, and pathologicallyexamined in contrast with the left kidneys of test compound-untreatedrats.

The results are shown in following Table 7.

                                      TABLE 7                                     __________________________________________________________________________                   The amount of the                                                                           The amount of the                                               serum creatinine                                                                            serum urine-nitrogen                                     The amount                                                                           (mg/dl)       (mg/dl)                                                  of the       Test compound Test compound                              Compound                                                                              administration                                                                       Control                                                                             administered-                                                                         Control                                                                             administered-                              No.     (mg/kg)                                                                              group group   group group                                      __________________________________________________________________________    34      0.1    4.94 ± 0.05                                                                      2.15 ± 0.22(***)                                                                   174.8 ± 4.0                                                                       78.6 ± 9.7(***)                        Aminophylline                                                                         10     2.03 ± 0.18                                                                      1.72 ± 0.07                                                                         46.2 ± 6.5                                                                       30.6 ± 2.0(**)                         (Reference                                                                    compound)                                                                     Furosemide                                                                            10     3.22 ± 0.35                                                                      4.17 ± 0.41                                                                        110.7 ± 9.4                                                                      150.3 ± 13.7(**)                        (Reference                                                                    compound)                                                                     Control --     0.50 ± 0.02                                                                      --       15.2 ± 0.9                                                                      --                                         __________________________________________________________________________     (***P < 0.001,                                                                **P < 0.05)                                                              

Values in test compound-treated group were compared to those in controlgroup using the Student's t-test (n=8˜10).

According to the results, Compound 34 significantly suppressed increasesin the serum creatinine and in serum urine-nitrogen, when administeredabdominally at a dosage of 0.1 mg/kg [i.p.] whereas aminophylline (10mg/kg) had a weak effect of suppressing the increase. On the contrary,furosemide (10 mg/kg) showed a tendency to increase the serumcreatinine. The pathological examination of removed kidney indicatesthat compound 34 also significantly improved the state of kidney.

Compound (I) or its pharmaceutically acceptable salts can be used assuch or in various medicament forms. The present pharmaceuticalcomposition can be prepared by uniformly mixing an effective amount ofCompound (I) or its pharmaceutically acceptable salts as an activecomponent with a pharmaceutically acceptable carrier. The pharmaceuticalcomposition is desirably in a unit dosage form applicable to oral orinjection administration.

In the preparation of pharmaceutical compositions in an oral dosageform, some useful, pharmaceutically acceptable carrier can be used. Forexample, liquid, orally administerable compositions such as suspensioncompositions or syrup compositions can be prepared with water, asaccharide such as sucrose, sorbitol, fructose, etc., a glycol such aspolyethyleneglycol, propyleneglycol, etc., an oil such as sesame oil,olive oil, soybean oil, etc., an antiseptic such as p-hydroxybenzoicacid esters, etc., and a flavor such as strawberry flavor, peppermint,etc. Powder, pills, capsules and tablets can be prepared with a vehiclesuch as lactose, glucose, sucrose, mannitol, etc., a disintegrator suchas starch, sodium alginate, etc., a lubricant such as magnesiumstearate, talc, etc., a binder such as polyvinyl alcohol, hydroxypropylcellulose, gelatin, etc., a surfactant such as fatty acid esters, etc.,a plasticizer such as glycerin, etc. and so forth. Tablets and capsulesare most useful unit for oral administration because of easyadministration. In the preparation of tablets or capsules, a solidpharmaceutical carrier is used.

Injection solutions can be prepared with a carrier such as distilledwater, saline solution, glucose solution, or a mixture of salinesolution and glucose solution.

Effective dosage and number of administration of Compound (I) or itspharmaceutically acceptable salts depend on the administration route andages, body weights, symptoms, etc. of patients, and it is preferable tousually administer Compound (I) at a dosage of 1 to 50 mg/kg per day in3 to 4 divisions.

Compound (I) and pharmacologically acceptable salts thereof can also beadministered by inhalation in the form of aerosol, finely dividedpowders or sprayed mist. In the case of aerosol administration, thecompounds according to the invention can be dissolved in an appropriate,pharmacologically acceptable solvent (e.g., ethyl alcohol) or a mixtureof miscible solvents, and then admixed with a pharmacologicallyacceptable propellant. Such an aerosol composition can be charged in apressure container equipped with an appropriate aerosol valve suited forthe spraying of the aerosol composition. It can be preferable to use anaerosol valve which is capable of spraying a predetermined quantity ofaerosol composition to provide an effective dosage thereof.

The present invention will be described below, by the following Examplesand Reference Examples.

EXAMPLE 18-[(1R*,4S*,5S*)-2-Bicyclo[2.2.1]hepten-5-yl]-1,3-dipropylxanthine(Compound 1), and 8-[(1R*, 4S*,5R*)2-bicyclo[2.2.1]hepten-5-yl]-1,3-dipropylxanthine (Compound 2)

At first, 2.57 g (18.6 mmol) of bicyclo[2,2,1]-5-heptane-2-carboxylicacid and 3.06 g (16.0 mm (3-dimethylaminopropyl)carbodiimidehydrochloride were added to a solution of 3.00g (13.3 mmol) of1,3-dipropyl-5,6-diaminouracil [U.S. Pat. No. 2,607,295 and J. Org.Chem., 16, 1879 (1951)] in 60 ml of dioxane and 30 ml of water and themixture was stirred at room temperature for 1 hour, while adjusting thepH to 5.5. The pH of the mixture is adjusted to 7.0, and the mixture wasextracted with chloroform three times, and the extract was washed with asaturated aqueous sodium chloride and dried over anhydrous sodiumsulfate. Then, the solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography (eluent: 2.0%methanol/chloroform) to afford 4.07 g (yield: 88%) of amorphous6-amino-5-(2-bicyclo[2,2,1]hepten-5-yl)carbonylamino-1,3-dipropyluracil.

NMR (CDCl₃, 90 MHz) δ(ppm): 7.20 (brs, 1H), 6.22-5.95 (m, 2H), 5.35(brs, 2H), 4.00-3.65 (m, 4H), 3.52-2.80 (m, 3H) and 2.20-0.80 (m, 14H)

Then, 40 ml of dioxane and 40 ml of 2N sodium hydroxide aqueous solutionwere added to 3.99 g (11.5 mmol) of the thus obtained compound and themixture was refluxed under heating for 20 minutes. After cooling, themixture was neutralized and extracted with chloroform three times. Then,the extract was washed with a saturated aqueous sodium chloride anddried over anhydrous sodium sulfate, and then the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: 25% ethyl acetate/hexane) and recrystallizedfrom cyclohexane to afford 1.97 g (yield: 52%) of the captioned Compound1 as a white powder and 0.63 g (yield: 18%) of the captioned Compound 2as a white powder.

Compound 1

Melting point: 121.6°-122.8° C. (recrystallized from isopropanol/water)

Rf value: 0.30 [TLC plate silica gel 60F₂₅₄ (product of Merck Co.,eluent: 30% ethylacetate/hexane]

Elemental analysis: C₁₈ H₂₄ N₄ O₂

Calculated (%): C 65.83, H 7.37, N 17.06

Found (%) C 65.71, H 7.51, N 16, 78

IR (KBr) vmax (cm⁻¹): 1,698, 1,653, 1,497

NMR (DMSO-d₆) δ(ppm): 12.84 (s, 1H), 6.17 (dd, J=3.2, 5.6 Hz, 1H), 5.72(dd, J=2.7, 5.6 Hz, 1H), 3.91 (t, 2H), 3.82 (t, 2H), 3.43 (ddd, J=4.2,4.2, 9.3 Hz, 1H), 3.28 (brs, 1H), 2.92 (brs, 1H), 2.08 (ddd, J=3.7, 9.3,13.0 Hz, 1H), 1.75-1.50 (m, 5H), 1.45-1.35 (m, 2H) and 0.90-0.80 (m, 6H)

Compound 2

Melting point: 167.6°-168.0° C. (recrystallized from ethanol/water)

Elemental analysis: C₁₈ H₂₄ N₄ O₂

Calculated (%): C 65.83, H 7.37, N 17.06

Found (%) C 66.03, H 7.69, N 17.09

Rf value: 0.46 (30% ethyl acetate/hexane)

IR (KBr) νmax (cm⁻¹): 1,695, 1,657, 1,495

NMR (DMSO-d₆) δ(ppm): 13.11 (brs, 1H), 6.21 (d, J=1.4 Hz, 2H), 3.95 (t,2H), 3.84 (t, 2H), 2.96 (brs, 2H), 2.63 (ddd, J=0.7, 4.2, 8.2 Hz, 1H),2.10 (ddd, J=4.2, 4.2, 11.5 Hz, 1H), 1.75-1.45 (m, 5H), 1.35-1.22 (m,2H), 0.92-0.80 (m, 6H).

EXAMPLE 28-[(1R*,2S*,5S*)-Bicyclo[2,2,1]heptan-2-yl]-1,3-dipropylxanthine(Compound 3) and 8-[(1R*, 2R*,5S*)-bicyclo[2.2.1)heptan-2-yl]-1,3-dipropylxanthine (Compound 4)

The substantially same operations as in Example 1 were repeated using3.0g (13.3 mmol) of 1,3-dipropyl-5,6-diaminouracil and 2.61g (18.6 mmol)of bicyclo[2.2.1]heptane-2-carboxylic acid to afford 4.31g (yield: 93%)of amorphous6-amino-5-(bicyclo[2.2.1]heptan-2-yl)carbonylamino-1,3-dipropyluracil.

NMR (CDCl₃, 90 MHz) δ(ppm): 7.21 (brs, 1H), 5.40 (brs, 25, 2H),4.00-3.70 (m, 4H), 3.00 -2.75 (m, 1H), and 2.65-0.75 (m, 20H)

The substantially same cyclization reaction as in Example 1 wasperformed using 4.30g (12.3 mmol) of the thus obtained compound, toafford 3.05g (yield: 75%) of8-bicyclo[2.2.1]heptan-2-yl)-1,3-dipropylxanthine [a mixture of (1R*,2S*, 5S*) isomer (Compound 3) and (1R*, 2R*, 5S*) isomer (Compound 4)]as a white powder. The mixture was subjected to high performance liquidchromatography (HPLC) [column, R-354 (30 cm×50 mmφ) (by Yamamura KagakuK. K.); eluent, 85% methanol/water; flow rate, 50 ml/min.] to afford 327mg of the captioned Compound 3 and 442 mg of the captioned Compound 4.

Compound 3

Melting point: 150.9°-152.0° C. (recrystallized from isopropanol/water)

Elementary analysis: C₁₈ H₂₆ N₄ O₂

Calculated (%): C 65.43, H 7.93, N 16.96

Found (%) C 65.41, H 8.11, N 17.00

IR (KBr) vmax (cm⁻¹): 1700, 1650, 1497.

NMR (DMSO-d6) 6(ppm): 13.00 (brs, 1H), 3.97 (t, 2H),

3.84 (t, 2H), 3.21 (ddd, J=4.2, 4.2, 11.6 Hz, 1H), 2.55 (brs, 1H), 2.28(brs, 1H), 1.90-1.22 (m, 11H), 1.15-1.03 (m, 1H), 0.95-0.82 (m, 6H).

HPLC [AM-312 (15 cm×5 mmφ) (by Yamamura Kagaku K. K.),

70% acetonitrile-water, UV 254 nm, 1.0 ml/min]:

Retention time; 12.7 min.

Compound 4

Melting point: 139.7°-142.9° C. (recrystallized from isopropanol/water)

Elementary analysis: C₁₈ H₂₆ N₄ O₂

Calculated (%): C 65.43, H 7.93, N 16.96

Found (%) C 65.66, H 8.29, N 16.90

IR (KBr) vmax (cm⁻¹): 1702, 1650, 1494.

NMR (DMSO-d₆) δ(ppm): 12.99 (brs, 1H), 3.94 (t, 2H), 3.83 (t, 2H), 2.79(dd, J=4.9,8.5 Hz, 1H), 2.39 (brs, 1H), 2.31 (brs, 1H), 2.08-1.96 (m,1H), 1.80-1.45 (m, 8H), 1.38-1.12 (m, 3H), 0.95-0.80 (m, 6H).

HPLC [AM-312 (15 cm×5 mmφ) (by Yamamura Kagaku K. K.)

70% acetonitrile-water, UV 254 nm, 1.0 ml/min]:

Retention time; 13.9 min.

In Examples 3 to 9 described below, the desired compounds were obtainedin the substantially same operations as in Example 1, except that acorresponding carboxylic acid was used instead ofbicyclo[2.1.1]-5-hepten-2-carboxylic acid. In those examples,intermediates obtained were used in the subsequent cyclization reactionswithout being isolated or purified.

EXAMPLE 38-[(1R*,2R*,5R*)-Bicyclo[3.3.0]octan-2-yl]-1,3-dipropylxanthine(Compound 5) and bicyclo[3.3.0]oxtan-2-yl]-1,3-dipropylxanthine(Compound 6)

The substantially same operations as in Example 1 were repeated using4.55 ml (31.9 mmol) of bicyclo[3.3.0]octane-2-carboxylic acid, and thefollowing two compounds were obtained.

Compound 5

Yield: 4.30 g (Yield, 47%; white plate crystal)

Melting point: 100.1°-101.6° C. (recrystallized from heptane)

Rf value: 0.53 (30% ethyl acetate/hexane)

Elementary analysis: C₁₉ H₂₈ N₄ O₂

Calculated (%): C 66.25, H 8.19, N 16.27

Found (%) C 66.07, H 8.43, N 16.61

IR (KBr) vmax (cm⁻¹): 1,699, 1,653 and 1,499

NMR(DMSO-d6) 6(ppm): 13.12 (brs, 1H), 3.94 (t, 2H), 3.83 (t, 2H),2.75-2.50 (m, 3H), 2.10-1.45 (m, 12H), 1.42-1.35 (m, 1H), 1.30-1.15 (m,1H), 0.95-0.85 (m, 6H)

¹³ C-NMR (CDCl₃) δ(ppm): 159.1, 155.7, 151.1, 149.4, 106.7, 50.4, 47.6,45.3, 43.4, 43.2, 34.4, 34.1, 33.6, 32.1, 25.1, 21.4, 11.4, 11.2.

Compound 6

Yield: 359 mg (Yield, 3.9%; white plate crystal)

Melting point: 118.4°-120.0° C. (recrystallized from heptane)

Rf value: 0.40 (30% ethyl acetate/hexane)

Elementary analysis: C₁₉ H₂₈ N₄ O₂

Calculated (%): C 66.25, H 8.19, N 16.27

Found (%) C 66.20, H 8.63, N 16.31

IR (KBr) νmax (cm⁻¹): 1,699, 1,652 and 1,497

NMR (CDCl₃) δ(ppm): 12.30 (brs, 1H), 4.11 (t, 2H), 4.02 (t, 2H), 3.30(ddd, 1H, J=6.8, 14 Hz), 3.00-2.85 (m, 1H), 2.70-2.53 (m, 1H), 2.25-0.90(m, 20H) ¹³ C-NMR (CDCl₃) δ(ppm): 157.0, 155.5, 151.2, 149.2, 106.5,47.6, 45.2, 44.0, 43.3, 42.9, 35.4, 32.5, 29.7, 27.5, 27.4, 21.4, 21.4,11.4, 11.2.

MS (m/e) relative intensity: 344 (M+, 100), 302 (28), 260 (18), 250 (23)and 230 (18)

EXAMPLE 4 8-[1-methyl-2-(4-pyridyl)ethyl]-1,3-dipropylxanthine (Compound7)

Overall yield: 79% (White needle crystal)

Melting point: 214.9°-217.3° C.

Elementary analysis: C₁₉ H₂₅ N₅ O₂.HCl.0.1H₂ O

Calculated (%): C 57.74, H 6.64, N 17.72

Found (%) C 57.79, H 6.54, N 17.63

IR (KBr) νmax (cm⁻¹) 1,704, 1,669 and 1,637

NMR (DMSO-d₆) δ(ppm): 13.50-12.80 (brs, 1H), 8.79 (d, 2H, J=6.1 Hz),7.84 (d, 2H, J=6.1 Hz), 3.90 (t, 2H), 3.81 (t, 2H), 3.50-3.20 (m, 3H),1.70-1.50 (m, 4H), 1.33 (d, 3H, J=6.7 Hz), 0.85 (t, 3H), 0.82 (t, 3H)

EXAMPLE 58-[1-Methyl-2-(2-methylthiazol-4-yl)ethyl]-1,3-dipropylxanthine(Compound 8)

Overall yield: 70% (White plate crystal)

Melting point: 137.6°-139.2° C. (recrystallized from cyclohexane)

Elementary analysis: C₁₈ H₂₅ N₅ O₂ S

Calculated (%): C 57.58, H 6.71, N 18.65

Found (%) C 57.75 H 6.72, N 18.48

IR (KBr) νmax (cm⁻¹): 1,698, 1,659 and 1,499

NMR (DMSO-d₆) δ(ppm): 13.11 (brs, 1H), 7.00 (s, 1H), 3.94 (t, 2H), 3.83(t, 2H), 3.45-3.10 (m, 3H), 2.92 (dd, 1H, J=6.8, 14.2 Hz), 2.59 (s, 3H),1.75-1.50 (m, 4H), 1.23 (d, 3H, J=6.8 Hz), 0.95-0.80 (m, 6H)

EXAMPLE 6 8-(Benzo[b]thiophen-2-yl)-1,3-dipropylxanthine (Compound 9)

Overall yield: 61% (White needle crystal)

Melting point: 307.9°-309.1° C. (recrystallized from ethanol)

Elementary analysis: C₁₉ H₂₀ N₄ O₂ S

Calculated (%): C 61.94, H 5.47, N 15.21

Found (%) C 61.91, H 5.44, N 15.15

IR (KBr) νmax (cm ⁻¹): 1,699, 1,642 and 1,537

NMR (DMSO-d₆) δ(ppm): 8.19 (s, 1H), 8.05-7.85 (m, 2H), 7.50-7.40 (m,2H), 4.00 (t, 2H), 3.87 (t, 2H), 1.85-1.50 (m, 4H), 1.00-0.80 (m, 6H)8-(Benzo[b]furan-2-yl)-1,3-dipropylxanthine

(Compound 10)

Overall yield: 71% (White needle crystal)

Melting point: 282.1°-283.9° C. (recrystallized from ethanol)

Elementary analysis: C₁₉ H₂₀ N₄ O₃

Calculated (%): C 64.76, H 5.72, N 15.90

Found (%): C 64.80, H 5.72, N 15.77

NMR (DMSO-d₆) δ(ppm): 14.30 (brs, 1H), 7.80-7.65 (m,

2H), 7.68 (s, 1H), 7.50-7.30 (m, 2H), 4.02 (t,

2H), 3.88 (t, 2H), 1.85-1.50 (m, 4H), 1.00-0.80

(m, 6H)

EXAMPLE 8 8-(3-Methylinden-2-yl)-1,3-dipropylxanthine Compound 11)

Overall yield: 36% (Light yellow plate crystal)

Melting point: 268.1°-269.9° C. (recrystallized from ethanol)

Elementary analysis: C₂₁ H₂₄ N₄ O₂

Calculated (%): C 69.21, H 6.64, N 15.37

Found(%) C 69.40, H 6.72, N 15.34

IR (KBr) νmax (cm⁻¹): 1,690, 1,641 and 1,485

NMR (DMSO-d₆) δ(ppm): 13.33 (brs, 1H), 7.55-7.45 (m, 2H), 7.40-7.25 (m,2H), 4.04 (t, 2H), 3.88 (s, 2H), 3.90-3.80 (m, 2H), 2.61 (s, 3H),1.85-1.50 (m, 4H), 0.95-0.80 (m, 6H)

Example 9 8-(2-Aminothiazol-4-yl)methyl-1,3-dipropylxanthine (Compound12

Overall yield: 94% (Light yellow plate crystal)

Melting point: 282.5°-284.3° C. (recrystallized from isopropanol)

IR (KBr) νmax (cm⁻¹) 1,697, 1,660, 1,523 and 1,500

NMR (DMSO-d6) 6 (ppm): 13.28 (brs, 1H), 6.89 (brs, 2H), 6.23 (s, 1H),4.00-3.80 (m, 4H), 3.86 (s, 2H), 1.80-1.50 (m, 4H), 0.95-0.80 (m, 6H)

MS (m/e) (Relative intensity): 348 (M+, 100), 306 (51), 277 (26), 264(47), 248 (28), 234 (86) and 113 (38)

Example 10 8-(Noradamantan-3-yl)-1,3-dipropylxanthine (Compound 14)

At first, 1.62 g (9.74 mmol) of 3-noradamantanecarboxylic acid wasdissolved in 30 ml of pyridine, and 0.78 ml (10.7 mmol) of thionylchloride was gradually added thereto at 0° C. After the mixture wasstirred for 30 minutes at room temperature, 2.00 g (8.85 mmol) of1,3-dipropyl-5,6-diaminouracil was gradually added thereto at 0° C.After stirring for 30 minutes at 0° C., the mixture was treated in thesame procedure as in Example 29, and the residue was subjected to silicagel column chromatography (eluent: 1% methanol/chloroform) to afford3.55 g (yield: 100%) of amorphous6-amino-5-(noradamantane-3-carbonylamino)-1,3-dipropyluracil.

NMR (90 MHz; CDCl₃) δ(ppm): 7.38 (brs, 1H), 5.62 (brs, 2H), 4.00-3.70(m, 4H), 2.90-2.60 (m, 1H), 2.40 -1.30 (m, 16H), 1.10-0.80 (m, 6H)

The substantially same cyclization reaction as in Example 29 wasperformed by reacting 2.90 g (7.55 mmol) of the thus obtained compoundwith phosphorus oxychloride to afford 509 mg (yield: 14%) of thecaptioned Compound 14 as a white needle crystal.

Melting point: 190.0°-191.0° C. (recrystallized from heptane)

Elementary analysis: C₂₀ H₂₈ N₄ O₂

Calculated (%): C 67.39, H 7.92, N 15.72

Found (%) C 67.41, H 7.62, N 15.78

IR (KBr) νmax (cm⁻¹): 1,699, 1,651 and 1,499

NMR (DMSO-d₆) δ(ppm): 12.97 (s, 1H), 3.95(t, 2H), 3.85 (t, 2H),2.70-2.60 (m, 1H), 2.35-2.26 (m, 2H), 2.20-2.10 (m, 2H), 1.95-1.82 (m,4H), 1.80-1.50 (m, 8H), 0.95-0.80 (m, 6H)

¹³ C-NMR (DMSO-d₆) 6 (ppm): 159.9, 153.9, 150.7, 147.6, 106.6, 48.8,48.2, 45.1, 44.2 , 43.2, 41.9, 36.9, 34.1, 20.8, 11.1, 10.9.

EXAMPLE 11 8-(Adamantan-1-yl)methyl-1,3-dipropylxanthine (Compound 15)

At first 2.00 g (8.85 mmol) of 1,3-dipropyl-5,6-diaminouracil and 2.06 g(10.6 mmol) of 1-adamantan acid were condensed according to theprocedure of Example 1 using1-ethyl-3-(3-dimethylaminopropyl)carbodiimide to afford 4.02 g (yield:100%) of amorphous6-amino-5-(adamantan-1-yl)acetylamino-1,3-dipropyluracil as a crudeproduct.

NMR (CDCl₃) δ(ppm): 7.42 (brs, 1H), 5.47 (brs, 2H), 4.00-3.70 (m, 4H),2.20-1.20 (m, 21H), 1.10 -0.80 (m, 6H)

The substantially same cyclization reaction as in Example 29 wasperformed by reacting 3.95 g of the thus obtained compound withphosphorus oxychloride to afford 1.66 g (overall yield: 49%) of thecaptioned Compound 15 as a white needle crystal.

Melting point: 177.7°-179.5° C. (recrystallized from isopropanol/water)

Elementary analysis: C₂₂ H₃₂ N₄ O₂

Calculated (%): C 68.72, H 8.39, N 14.57

Found (%) C 68.71, H 8.74, N 14.70

IR (KBr) νmax (cm⁻¹): 1,704, 1,648 and 1,498

NMR (DMSO-d6) 6(ppm): 13.06 (brs, 1H), 3.95 (t, 2H), 3.83 (t, 2H),3.40-3.25 (m, 2H), 2.43 (brs, 2H), 1.90 (brs, 3H), 1.80-1.45 (m, 16H),0.95-0.85 (m, 6H)

EXAMPLE 128-[(1lR*,2R*,5S*)-Bicyclo[2.2.1]heptan-2-yl]methyl-1,3-dipropylxanthine(Compound 16

Compound 16 was obtained in the same procedure as in Example 11, exceptfor using 1.54 ml (10.6 mmol) of(1R*,2R*,5S*)-bicyclo[2.2.1]heptane-2-acetic acid in place of1-adamantaneacetic acid.

Yield: 1.22 g (White needle crystal; overall yield, 40%)

Melting point: 119.9°-121.4° C. (recrystallized from isopropanol/water)

Elementary analysis: C₁₉ H₂₈ N₄ O₂

Calculated (%): C 66.25, H 8.19, N 16.27

Found (%) C 66.29, H 8.32, N 16.06

IR (KBr) νmax (cm⁻¹): 1,699, 1,654 and 1,502

NMR (CDCl₃) 6(ppm): 12.83 (brs, 1H), 4.15-4.00 (m, 4H), 2.81 (dd, 1H,J=7.8, 14.2 Hz), 2.66 (dd, 1H, J=7.8, 14.2 Hz), 2.26 (brs, 1H),2.15-2.00 (m, 2H), 1.95-1.65 (m, 4H), 1.60-1.40 (m, 4H), 1.30-0.90 (m,10)

EXAMPLE 13 8-[(1R*,4S*,5S*)-2-Bicyclo[2.2.1]hepten-5-yl]-1,3-dipropyl-7-methylxanthine(Compound 17)

At first 1.00 g (3.05 mmol) of8-[(1R*,4S*,5S*)-2-bicyclo[2.2.1]hepten-5-yl]-1 prepared in Example 1was dissolved in 30 ml of N,N'-dimethylformamide, and 1.05 g carbonateand 0.38 ml (6.10 mmol) of methyl iodide were added thereto. After themixture was stirring at 50° C. for 30 minutes under argon atmosphere,insoluble materials were filtered off, and the filtrate was concentratedunder reduced pressure. The residue was poured into 200 ml of water andthe mixture was extracted with chloroform three times. The organic layerwas combined, and the extract was washed with water and then with asaturated aqueous sodium chloride, and dried over anhydrous sodiumsulfate and then the solvent was evaporated under reduced pressure. Theresidue was subjected to silica gel column chromatography (eluent: 20%ethyl acetate/hexane) to afford 1.05 g (yield: 100%) of the captionedCompound 17 as a light yellow powder.

Melting point: 99.8°-103.1° C. (recrystallized from acetone/water)

Elementary analysis: C₁₉ H₂₆ N₄ O₂

Calculated (%): C 66.64, H 7.65, N 16.36

Found (%) C 66.60, H 7.97, N 16.55

(IR (KBr) νmax (cm⁻¹): 1698, 1666, 1652, 1445.

NMR (CDCl₃) δ(ppm): 6.19 (dd, J=3.0, 5.6 Hz, 1H), 5.87 (dd, J=2.8, 5.6Hz, 1H), 4.01 (t, 2H), 3.95 (t, 2H), 3.94 (s, 3H), 3.36-3.28 (m, 2H),3.00 (brs, 1H), 2.19 (ddd, J=3.9, 9.3, 11.5 Hz, 1H), 1.84-1.50 (m, 6H),1.45-1.40 (m, 1H), 1.00-0.90 (m, 6H).

EXAMPLE 148-[(1R*,2R*,5R*)-Bicyclo[3.3.0]octan-2-yl]-1,3-dipropyl-7-methylxanthine(Compound 18)

The substantially same operations as in Example 13 were repeated exceptfor using 1.00 g (2.90 mmol) of8-[(1R*,2R*,5R*)-bicyclo[3.3.0]octan-2-yl]-1,3-dipropylxanthine(Compound 5) prepared in Example 3 to afford 1.05 g (yield: 100%) of thecaptioned Compound 18 as a white powder.

Melting point: 94.7°-97.0° C. (recrystallized from ethanol/water)

Elementary analysis: C₂₀ H₃₀ N₄ O₂

Calculated (%): C 67.01, H 8.44, N 15.63

Found (%) C 66.93, H 8.20, N 15.68

IR (KBr) νmax (cm⁻¹): 1702, 1653.

NMR (CDCl₃) 6(ppm): 4.05 (t, 2H), 3.96 (t, 2H), 3.93 (s, 3H), 2.96-2.84(m, 1H), 2.80-2.64 (m, 2H), 2.20 -1.60 (m,11H), 1.48-1.25 (m, 3H),1.02-0.94 (m, 6H).

EXAMPLE 15 1,3-Dipropyl-7-methyl-8-(noradamantan-3-yl)xanthine (Compound20)

The substantially same operations as in Example 13 were repeated exceptfor using 2.20 g (6.18 mmol) of8-(noradamantan-3-yl)-1,3-dipropylxanthine (Compound 14) prepared inExample 10 to afford 1.06 g (yield: 46%) of the captioned Compound 20 asa white needle crystal.

Melting point: 123.2°-124.8° C. (recrystallized from ethanol/water)

Elementary analysis: C₂₁ H₃₀ N₄ O₂

Calculated (%): C 68.08, H 8.16, N 15.12

Found (%) C 67.93, H 8.23, N 15.44

IR (KBr) νmax (cm⁻¹): 1698, 1661.

NMR (CDCl₃) 6(ppm): 4.05 (t, 2H), 4.01 (s, 3H), 3.96 (t, 2H), 2.98(t,2H), 2.40 (brs, 2H), 2.25-2.17 (m,2H), 2.11-1.90 (m, 6H).

EXAMPLE 16 7-Ethyl-1,3-dipropyl-8-(noradamantan-3-yl)xanthine (Compound21)

The substantially same operations as in Example 13 were repeated exceptfor using 1.40 g (3.93 mmol) of8-(noradamantan-3-yl)-1,3-dipropylxanthine (Compound 14) prepared inExample 10 and 0.62 ml (7.87 mmol) of ethyl iodide to afford 410 mg(yield: 27%) of the captioned Compound 21 as a white crystal.

Melting Point: 91.3°-92.4° C. (recrystallized from acetonitrile)

Elementary analysis: C₂₂ H₃₂ N₄ O₂

Calculated (%): C 68.71, H 8.38, N 14.57

Found (%) C 68.88, H 8.59, N 14.69

IR (KBr) νmax (cm⁻¹): 1698, 1661, 1535.

NMR (CDCl₃, 90 MHz) δ(ppm): 4.34 (q, J=7.0 Hz, 2H), 4.20-3.86 (m, 4H),3.03 (t, 1H), 2.50-1.40 (m, 16H), 1.50 (t, J=7.0 Hz, 3H), 1.15-0.85 (m,6H).

EXAMPLE 17 3 8-(Noradamantan-3-yl)-1,3,7-tripropylxanthine (Compound 22)

The substantially same operations as in Example 13 were repeated exceptfor using 1.50 g (4.21 mmol) of8-(noradamantan-3-yl)-1,3-dipropylxanthine (Compound 14) prepared inExample 10 and 0.82 ml (8.43 mmol) of propyl iodide to afford 1.40 g(yield: 84%) of the captioned Compound 22 as a white crystal.

Melting point: 111.2°-112.2° C. (Recrystallized from ethanol/water)

Elementary analysis: C₂₃ H₃₄ N₄ O₂

Calculated (%): C 69.31, H 8.59, N 14.05

Found (%) C 69.29, H 8.69, N 14.57

IR (KBr) νmax (cm⁻¹): 1700, 1662, 1536.

NMR (CDCl₃, 90 MHz) 6(ppm): 4.30-3.85 (m, 6H), 3.05 (t, 1H), 2.50-1.50(m, 18H), 1.20-0.85 (m, 6H).

EXAMPLE 18 8-[(1R*, 2R*, 5R*)-Bicyclo[3.3.0]octan-2-yl]-3-propylxanthine (Compound 23)

Af first, 100 ml of N,N'-dimethylformamide was suspended in 5.00 g (27.2mmol) of 5,6-diaminouracil [Japanese Published Unexamined PatentApplication No. 57,517/80] and 3.88 ml (27.2 mmol) ofbicyclo[3.3.0]octan-2-carboxylic acid, 8.40 g (40.8 mmol) ofN,N'-dicyclohexylcarbodiimide and then 5.00 g (32.6 mmol) ofN-hydroxybenztriazole were added thereto. After the mixture was stirredovernight at room temperature, insoluble materials were filtered off,and the filtrate was concentrated under reduced pressure. 100 ml ofaqueous 4N sodium hydroxide solution was added to the residue, and themixture was refluxed under heating for 20 minutes. After cooling, themixture was neutralized with concentrated hydrochloric acid, and theprecipitated crystals were collected by filtration. 500 ml of water wasadded to the resulting crystals, and the mixture was extracted withchloroform three times. The combined extract was washed with a saturatedaqueous sodium chloride and dried over anhydrous sodium sulfate, andthen the solvent was evaporated under reduced pressure. The obtainedcrude crystals were recrystallized from ethanol-water to afford 3.68 g(yield: 45%) of the captioned Compound 23 as a white needle crystal.

Melting point: 252.8°-257.9° C. (recrystallized from ethanol/water)

Elementary analysis: C₁₆ H₂₂ N₄ O₂

Calculated (%): C 63.55, H 7.33, N 18.53

Found (%) C 63.40, H 7.67, N 18.88

IR (KBr) νmax (cm⁻¹): 1700, 1678.

NMR (DMSO-d₆) 6(ppm): 13.03 (brs, 1H), 10.88 (brs, 1H), 3.87 (t, 2H),2.72-2.50 (m, 3H), 2.10-1.15 (m, 12H), 0.87 (t, 3H).

EXAMPLE 198-[(1R*,2R*,5R*)-Bicyclo[3.3.0]octan-2-yl]-1,3-dipropyl-2-thioxanthine(Compound 24)

The substantially same operations as in Example 1 were repeated exceptfor using 2.00 g (8.26 mmol) of 5,6-diamino-1,3-dipropyl-2-thiouracil[J. Med. Chem., 32, 1873 (1989)] and 1.42 ml (9.92 mmol) ofbicyclo[3.3.0]octan-2-carboxylic acid to afford 1.70 g (overall yield:57%) of the captioned Compound 24 as a white crystal.

Melting point: 135.1°-137.2° C. (recrystallized from ethanol)

Elementary analysis: C₁₉ H₂₈ N₄ OS

Calculated (%): C 63.30, H 7.83, N 15.54

Found (%) C 63.54, H 8.14, N 15.59

IR (KBr) νmax (cm⁻¹): 1688, 1493.

NMR (CDCl₃) δ(ppm): 12.68 (brs, 1H), 4.68 (t, 2H), 4.63 (t, 2H),2.92-2.65 (m, 3H), 2.25-1.53 (m, 12H), 1.50-1.43 (m, 1H), 1.41-1.22 (m,1H), 1.15 -0.98 (m, 6H).

HPLC [AM-312 (15 cm×5 mmφ) (by Yamamura Kagaku K. K.), 70%acetonitrile-water, UV 254 nm, 2.0 ml/min]: Retention time; 14.4 min.

EXAMPLE 20

8-(Noradamantan-3-yl)-3-propylxanthine (Compound 25)

The substantially same operations as in Example 10 were repeated exceptfor using 2.00 g (10.9 mmol) of 1-propyl-5,6-diaminouracil to afford2.27 g (yield: 63%) of6-amino-5-(noradamantane-3-carbonylamino)-3-propyluracil as a lightyellow powder.

NMR (DMSO-d₆, 90 MHz) δ(ppm): 10.47 (brs. 1H), 7.63 (brs, 1H), 6.23(brs, 2H), 3.78 (t, 2H), 2.71 (t, 1H), 2.32-1.38 (m, 14H), 0.89 (t, 3H).

The substantially same cyclization reaction as in Example 1 wasperformed using 2.16 g (6.51 mmol) of the thus obtained compound and 40ml of a 2N sodium hydroxide aqueous solution to afford 1.85 g (yield:91%) of the captioned Compound 25 as a white crystal.

Melting point: >290° C. (from dioxane/water)

Elementary analysis: C₁₇ H₂₂ N₄ O₂

Calculated (%): C 64.94, H 7.05, N 17.82

Found (%) C 64.65, H 7.20, N 18.00

IR (KBr) νmax (cm^(-b) 1): 1698, 1660, 1500.

NMR (DMSO-d₆, 90 MHz) 6(ppm): 12.42 (brs, 1H), 11.90 (brs, 1H), 4.08 (t,2H), 2.77 (t, 1H) 2.55-1.40 (m, 14H), 1.00 (t, 3H).

EXAMPLE 21 8-(Noradamantan-3-yl)-3-propyl-6-thioxanthine (Compound 26)

Af first, 20.0 g (63.7 mmol) of 8-(noradamantan-3-yl)-3-propylxanthine(Compound 25) prepared in Example dissolved in 370 ml of pyridine, and23.1 g (104 mmol) of phosphorus pentasulfide was added thereto. Themixture was refluxed under heating for 4 hours and poured into icewater, and the solid substances deposited were collected by filtration.The filtrate was concentrated under reduced pressure, and the solidsubstances deposited were again collected by filtration. The depositedsolid substances were combined and dissolved in 200 ml of 2N sodiumhydroxide solution, and insoluble materials were filtered off. Thefiltrate was neutralized with concentrated hydrochloric acid, and thedeposited crystals were collected by filtration. The crude crystals wererecrystallized from ethanol-water to afford 11.7 g (yield: 56%) of thecaptioned Compound 26 as a light yellow needle crystal.

Melting point: 214.2°-216.0° C. (recrystallized from ethanol/water)

Elementary analysis: C₁₇ H₂₂ N₄ OS.1/5H₂ O

Calculated (%): C 61.12, H 6.76, N 16.77

Found (%) C 61.12, H 6.82, N 16.95

IR (KBr) νmax (cm⁻¹): 1668, 1595.

NMR (CDCl₃, 90 MHz) 6(ppm): 10.14 (brs, 1H), 9.43 (brs, 1H), 4.05 (t,2H), 2.73 (t, 1H), 2.68-1.40 (m, 14H), 0.98 (t, 3H).

EXAMPLE 22 8-(Noradamantan-3-yl)-1,3-dimethylxanthine (Compound 27)

The substantially same operations as in Example 10 were repeated exceptfor using 3.00g (17.6 mmol) of 1,3-dimethyl-5,6-diaminouracil instead of1,3-dipropyl-5,6-diaminouracil [J. Am. Chem. Soc., 76, 2798 (1954)] toafford 3.61 g (yield: 65%) of6-amino-5-(noradamantane-3-carbonylamino)-1,3-dimethyluracil as a lightyellow powder.

NMR (DMSO-d₆, 90 MHz) 6 (ppm): 7.68 (brs, 1H), 6.28 (brs, 2H), 3.30 (s,3H), 3.11 (s, 3H), 2.71 (t, 1H), 2.66-1.40 (m, 12H).

The substantially same cyclization reaction as in Example 1 wasperformed except for using 3.60 g (11.3 mmol) of the thus obtainedcompound to afford 2.41 g (yield: 71%) of the captioned Compound 27 as awhite crystal.

Melting point: >295° C. (recrystallized from ethanol/water)

Elementary analysis: C₁₆ H₂₀ N₄ O₂

Calculated (%): C 63.98, H 6.71, N 18.65

Found (%) C 63.97, H 6.78, N 18.89

IR (KBr) νmax (cm⁻¹): 1719, 1656, 1649, 1503.

NMR (CDCl₃, 90 MHz) δ(ppm): 11.93 (brs, 1H), 3.62 (s, 3H), 3.46 (s, 3H),2.79 (t, 1H), 2.52-1.60 (m, 12H).

EXAMPLE 23 8-(Noradamantan-3-yl)-1,3-diethylxanthine (Compound 28)

The substantially same operations as in Example 10 were repeated using2.0 g (10.1 mmol) of 1,3-diethyl-5,6-diaminouracil [J. Am. Chem. Soc.,75, 114 (1953)9 to afford 2.01 g (yield: 58%) of6-amino-5-(noradamantane-3-carbonylamino)-1,3-diethyluracil as a lightyellow powder

NMR (CDCl₃, 90 MHz) 6 (ppm): 7.35 (brs, 1H), 5.61 (brs, 2H), 4.18-3.85(m, 4H), 2.76 (t, 1H), 2.50-1.10 (m, 18H).

The substantially same cyclization reaction as in Example 1 wasperformed except for using 1.90 g (5.49 mmol) of the thus obtainedcompound to afford 1.58 g (yield: 88%) of the captioned Compound 28 as awhite crystal.

Melting point: 259.8°-263.1° C. (recrystallized from ethanol/water)

Elementary analysis: C₁₈ H₂₄ N₄ O₂

Calculated (%): C 65.83, H 7.36, N 17.05

Found (%) C 65.99, H 7.51, N 17.30

IR (KBr) νmax (cm⁻¹): 1704, 1646, 1497.

NMR (CDCl₃, 90 MHz) 6 (ppm): 11.93 (brs, 1H), 4.40 -3.98 (m, 4H), 2.83(t, 1H), 2.60-1.60 (m, 16H), 1.50-1.18 (m, 6H).

EXAMPLE 24 8-(Noradamantan-3-yl)-1,3-dibutylxanthine (Compound 29)

The substantially same operations as in Example 10 were repeated exceptfor using 1.70 g (6.69 mmol) of 1,3-dibutyl-5,6-diaminouracil (U.S. Pat.No. 2,607,295) to afford 2.42 g (yield: 90%) of amorphous6-amino-5-(noradamantane-3-carbonylamino)-1,3-dibutyluracil.

NMR (CDCl₃, 90 MHz) 6 (ppm): 7.40 (brs, 1H), 5.59 (brs, 2H), 4.05-3.76(m, 4H), 2.76 (t, 1H), 2.50-0.80 (m, 24H).

The substantially same cyclization reaction as in Example 1 wasperformed using 2.08 g (5.17 mmol) of the thus obtained compound toafford 1.87 g (yield: 94%) of the captioned Compound 29 as a lightyellow powder.

Melting point: 159.7°-161.0° C. (recrystallized from ethanol/water)

Elementary analysis: C₂₂ H₃₂ N₄ O₂

Calculated (%): C 68.71, H 8.38, N 14.57

Found (%) C 68.69, H 8.23, N 14.81

IR (KBr) νmax (cm⁻¹): 1704, 1651, 1498.

NMR (CDCl₃, 90 MHz) 6 (ppm): 11.67 (brs, 1H), 4.28-3.90 (m, 4H), 2.82(t, 1H), 2.62-1.19 (m, 18H), 1.15-0.80 (m, 6H).

EXAMPLE 25 8-(Noradamantan-3-yl)-3-isobutyl-1-methylxanthine (Compound30)

The substantially same operations as in Example 10 were repeated exceptfor using 1.87 g (8.81 mmol) of 1-isobutyl-3-methyl-5,6-diaminouracil[Methods in Enzymology, 159, 489 (1988)] to afford 2.63 g (yield: 83%)of 6-amino-5-(noradamantane-3-carbonylamino)-1-isobutyl -3methyluracilas a white powder.

NMR (CDCl₃, 90 MHz) 6 (ppm): 7.35 (brs, 1H), 5.56 (brs, 2H), 3.77 (d,J=7.7 Hz, 2H), 3.34 (s, 3H), 2.76 (t, 1H), 2.40-1.50 (m, 13H), 0.99 (d,J=6.6 Hz, 6H)

The substantially same cyclization reaction as in Example 1 wasperformed except for using 2.60 g (7.21 mmol) of the thus obtainedcompound to afford 1.69 g (yield: 68%) of the captioned Compound 30 as awhite needle crystal.

Melting point: 266.0°-268.7° C. (recrystallized from ethanol/water)

Elementary analysis: C₁₉ H₂₆ N₄ O₂

Calculated (%) C 66.64, H 7.65, N 16.36

Found (%) C 66.89, H 7.44, N 16.42

IR (KBr) νmax (cm⁻¹): 1708, 1652, 14

NMR (CDCl₃, 90 MHz) 6 (ppm) 11.72 (brs, 1H), 3.98 (d, J=7.5 Hz, 2H),3.44 (s, 3H), 2.77 (t, 1H}, 2.52-1.60 (m, 13H), 0.95 (d, J=6.6 Hz, 6H).

EXAMPLE 26 8-(Noradamantan-3-yl)-1,3-dipropyl-2-thioxanthine (Compound31)

The substantially same operations as in Example 10 were repeated exceptfor using 3.00 g (12.4 mmol) of 5,6-diamino-1,3-dipropyl-2-thiouraciland 2.27 g (13.6 mmol) of noradamantane-3-carboxylic acid to afford 2.95g (yield: 60%) of amorphous6-amino-5-(noradamantane-3-carbonylamino)-1,3-dipropyl-2-thiouracil.

NMR (CDCl₃, 90 MHz) 6 (ppm): 7.50 (brs, 1H), 5.80 (brs, 2H), 4.60-4.25(m, 4H), 2.72 (t, 1H), 2.40-1.50 (m, 16H), 1.20-0.80 (m, 6H).

The substantially same cyclization reaction as in Example 29 wasperformed except for using 2.70 g (6.92 mmol) of the thus obtainedcompound instead of6-amino-5-(adamantane-1-carbonylamino)-1,3-dipropyluracil to afford 765mg of the captioned Compound 31 as a light yellow powder.

Melting point: 216.2°-216.6° C. (recrystallized from isopropanol)

Elementary analysis: C₂₀ H₂₈ N₄ OS

Calculated (%) C 64.48, H 7.58, N 15.04

Found (%) : C64.49, H 7.56, N 15.35

IR (KBr) νmax (cm⁻¹): 1690, 1494.

NMR (CDCl₃) 6 (ppm): 11.96 (brs, 1H), 4.69 (t, 2H), 4.61 (t, 2H), 2.86(t, 1H), 2.48-2.42 (m, 2H), 2.35-2.26 (m, 2H), 2.15-1.85 (m, 12H),1.15-0.95 (m, 6H).

Example 27 8-(Noradamantan-3-yl)-1,3-dipropyl-6-thioxanthine (Compound32)

The substantially same operations as in Example 21 were repeated exceptfor using 2.00 g (5.62 mmol) of8-noradamantan-3-yl)-1,3-dipropylxanthine (Compound 14in Example 10 toafford 2.02 g (yield: 70%) of the captioned Compound 32 as a lightyellow crystal.

Melting point: 128.5°-130.4° C. (recrystallized from acetonitrile)

Elementary analysis: C₂₀ H₂₈ N₄ OS

Calculated (%): C 64.48, H 7.58, N 15.04

Found (%) C 64.49, H 7.66, N 15.29

IR (KBr) νmax (cm⁻¹): 1,682, 1,597 and 1,495

NMR (CDCl₃, 90 MHz) 6 (ppm): 9.65 (brs, 1H), 4.43 (t, 2H), 4.06 (t, 2H),2.69 (t, 1H), 2.53-1.60 (m, 16H), 1.10-0.85 (m, 6H).

EXAMPLE 28 8-(Noradamantan-3-yl)-1,3-dipropyl-2,6-dithioxanthine(Compound 33)

The substantially same operations as in Example 21 were repeated exceptfor using 2.00 g (5.38 mmol) of8-noradamantan-3-yl)-1,3-dipropyl-2-thioxanthine (Compound 31) preparedin Example 26 to afford 1.27 g (yield: 61%) of the captioned Compound 33as a light yellow powder.

Melting point: 94.2°-96.6° C. (recrystallized from acetonitrile)

Elementary analysis: C₂₀ H₂₈ N₄ S₂ 0.1CH₃ CN.0.2H₂ 0

Calculated (%): C 61.22, H 7.30, N 14.49

Found (%) C 61.18, H 7.38, N 14.57

IR (KBr) νmax (cm⁻ 1): 1604, 1504, 1088.

NMR (CDCl₃, 90 MHz) 6 (ppm): 9.46 (brs, 1H), 5.06 (t, 2H), 4.62 (t, 2H),2.72 (t, 1H), 2.53-1.55 (m, 16H), 1.15-0.85 (m, 6H).

Example 29 8-(Adamantan-1-yl)-1,3-dipropylxanthine (Compound 13)

At first, 10 g (44.3 mmol) of 1,3-dipropyl-5,6-diaminouracil wasdissolved in 50 ml of pyridine, and 10.6 g (53.1 mmol) ofadamantane-1-carbonylchloride was added by portions thereto at 0° C.After stirring for 30 minutes at 0° C., the mixture was concentratedunder reduced pressure. A saturated aqueous sodium bicarbonate was addedthereto. The residue was extracted with chloroform three times. Theorganic layers were combined, washed with a saturated aqueous sodiumchloride, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. Then pyridine was removed from theresidue by means of azeotropy with toluene to afford 19.5 g (yield:100%) of 6-amino-5-(adamantane-1-carbonylamino)-1,3-dipropyluracil.

NMR (90MHz; CDCl₃) 6 (ppm): 7.47 (brs, 1H), 5.60 (brs, 2H), 4.05-3.70(m, 4H), 2.25-1.45 (m, 19H), 1.15 -0.85 (m, 6H)

Then, 100 ml of phosphorus oxychloride was added to 19.5 g of the thusobtained compound and the mixture was refluxed under heating for 30minutes. The mixture was concentrated under reduced pressure, and asaturated aqueous sodium bicarbonate was added to the residue. Theresidue was extracted with chloroform three times. The extract was driedover anhydrous sodium sulfate and then the solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography (eluent: 20% ethyl acetate/hexane) and recrystallizedfrom isopropanol-water to afford 2.07 g (overall yield: 13%) of thecaptioned Compound 13 as a white needle crystal.

Melting point: 169.3°-171.0° C.

Elementary analysis: C₂₁ H₃₀ N₄ O₂

Calculated (%): C 68.08, H 8.16, N 15.12

Found (%) C 68.10, H 8.30, N 15.09

IR (KBr) νmax (cm⁻¹): 1699, 1650, 1491

NMR (CDCl₃) 6 (ppm): 11.70 (brs, 1H), 4.15-3.95 (m, 4H), 2.15-2.05 (m,9H), 1.85-1.50 (m, 10H), 1.05 -0.85 (m, 6H)

EXAMPLE 30 8-(Adamantan-1-yl)-1,3-dipropyl-7-methylxanthine (Compound19)

The substantially same operations as in Example 13 were repeated exceptfor using 2.50 g (6.76 mmol) of 8-(adamantan-1-yl)-1,3-dipropylxanthine(Compound 13) prepared in Example 29 to afford 2.16 g (yield: 83%) ofthe captioned Compound 19 as a white crystal.

Melting point: 79.8°-80.9° C. (recrystallized from ethanol/water)

Elementary analysis: C₂₂ H₃₂ N₄ O₂

Calculated (%): C 68.17, H 8.38, N 14.57

Found (%) C 68.28, H 8.47, N 14.72

IR (KBr) νmax (cm⁻¹): 1698, 1659.

NMR (DMSO-d₆) 6 (ppm): 4.10 (s, 3H), 3.93 (t, 2H), 3.82 (t, 2H),2.13-2.02 (m, 9H), 1.82-1.46 (m, 10H), 0.90-0.80 (m, 6H).

EXAMPLE 31 1,3-Diallyl-8-(3-noradamantyl)xanthine (Compound 34)

At first, 1.65 g (9.91 mmols) of 3-noradamantanecarboxylic acid wasdissolved in 20 ml of pyridine, and 0.80 ml (10.8 mmols) of thionylchloride was added dropwise thereto at 0° C. The mixture was stirred for1 hour at room temperature, and cooled to 0° C. once again. 2.00 g (9.01mmols) of 5,6-diamino-1,3-diallyluracil [NaunynSchmiedeberg's Arch.Pharmacol., 336, 204 (1987)] in 20 ml of a methylene chloride solutionwas added dropwise. The reaction mixture was further stirred for 1 hourat room temperature, and concentrated under reduced pressure. Theconcentrate was poured into 100 ml of water. The mixture was extractedwith 30 ml of chloroform three times. The organic layers were combined,washed with a saturated aqueous sodium chloride, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified and isolated by silica gel columnchromatography (eluent: 2% methanol/chloroform) to afford 2.44 g (yield:73%) of 6-amino-1,3-diallyl-5-(noradamantane-3-carbonylamino)uracil asamorphous.

NMR (90 MHz; CDCL₃)δ(ppm): 7.41 (1H, brs), 6.20-5.10 (8H, m), 4,80˜4.45(4H, m), 2.76 (1H, t), 2.50˜1.50 (12H, m).

Then, 27 ml of 2N sodium hydroxide aqueous solution and 14 ml of dioxanewere added to 2.29 g (6.19 mmols) of the obtained compound and themixture was refluxed under heating for 1 hour. After cooling, thereaction mixture was neutralized with concentrated hydrochloric acid,and extracted three times with chloroform. Then the organic layers werecombined, washed with a saturated aqueous sodium chloride and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The obtained crude crystals were recrystallized fromisopropanol-water to afford 1.55 g (yield: 71%) of Compound 34 as awhite needle crystal.

Melting point: 202.0-204.3° C

Elemental analysis: C₂₀ H₂₄ N₄ O₂

Calculated (%): C68.16, H 6.86, N 15.89

Found (%): C 68.20, H 6.97, N 15.63

IR (KBr) νmax (cm⁻¹): 3190, 2940, 1704, 1658, 1651, 1550, 1498

NMR 90 MHz; CDCl₃)δ(ppm): 6.30˜5.70 (2H, m), 5.60˜5.00 (4H, m),4.90˜4.60 (4H, m), 2.80 (1H, t), 2.55˜1.50 (12H, m)

MS (m/e): 352 (M⁺).

EXAMPLE 32 3-Allyl-8-(3-noradamantyl)-1-propargylxanthine Compound 35

At first, 1.10 g (3.21 mmols) or 3-allyl-8-(3-noradamantyl)xanthineobtained in reference Example 1 was dissolved in 32 ml ofdimethylformamide, and 257 mg (6.42 mmols) of 60% sodium hydride wasadded at 0° C. After the mixture was stirred for 30 minutes at roomtemperature, 0.25 ml (3.36 mmols) of propargyl bromide was dropwiseadded thereto. The mixture was stirred for 4 hours at room temperature,and the reaction mixture was poured into 300 ml of water and wasneutralized with 1N hydrochloric acid. The mixture was extracted with 50ml of chloroform three times. The organic layers were combined, washedwith water twice and then with a saturated aqueous sodium chloride, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified and isolated by flushchromatograaphy (eluent: 40% ethyl acetate/hexane) and recrystallizedfrom dimethysulfoxide-water to afford 110 mg (yield: 23%) of Compound 35as a white powder.

Melting point: 256.3-257.1° C.

Elemental analysis: C₂₀ H₂₂ N₄ O₂

Calculated (%): C 68.55, H 6.32, N 15.98

Found (%): C 68.62, H 6.45, N 16.05

IR (KBr) νmax (cm⁻¹): 1700, 1659, 1649, 1548, 1496

NMR (270 MHz; CDCl₃) δ(ppm): 11.58 (1H, brs), 6.10˜5.90 (1H, m),5.45˜5.20 (2H, m), 4.90˜4.70 (4H, m), 2.80 (1H, t), 2.50˜1.90 (8H, m),1.80˜1.60 (5H, m).

MS (m/e): 350 (M⁺).

REFERENCE EXAMPLE 1 3-Allyl-8-(3-noradamantyl)xanthine

At first, 3.22 g (19.4 mmols) of 3-noradamantanecarboxylic acid wasdissolved in 80 ml of pyridine, and 1.54 ml (21.1 mmols) of thionylchloride was dropwise added under ice-cooling. The mixture was stirredfor 50 minutes at room temperature. 3.21 g (17.6 mmols) of1-allyl-5,6-diaminouracil (U.S. Pat. No. 2,673,848) was gradually addedto the reaction mixture under ice-cooling. After stirring for 2 hours atroom temperature, the reaction mixture was concentrated under reducedpressure. The residue was extracted five times with chloroform/methanol(5/1). The organic layers were combined and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. 30 ml ofdioxane and 60 ml of aqueous 1N sodium hydroxide solution were added tothe residue, and the mixture was refluxed under heating for 30 minutes.After cooling, the reaction mixture was neutralized with 1N hydrochloricacid, and was extracted three times with 50 ml of chloroform. Theorganic layers were combined, washed with a saturated aqueous sodiumchloride and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to afford 4.92 g (yield: 90%) of thecaptioned Compound as a light yellow plate crystal.

Melting point: >270° C. (recrystallized from ethanol/water)

Elemental analysis: C₁₇ H₂₀ N₄ O₂

Calculated (%): C 65.36, H 6.45, N 17.93

Found (%): C 64.98, H 6.72, N 17.86

IR (KBr) νmax (cm⁻¹): 1685, 1648, 1643, 1498, 1425

NMR (90 MHz; CDCl₃) δ(ppm): 12.10 (1H, brs), 7.20 (1H, s), 6.20˜5.65(1H, m), 5.45˜5.05 (2H, m), 4.80˜4.45 (2H, m), 2.71 (1H, t), 2.55˜1.50(12H, m).

Pharmaceutical Preparation 1 Tablet

A tablet having the following composition was prepared according to theconventional method

    ______________________________________                                        Compound 3        20 mg                                                       Lactose           60 mg                                                       Potato starch     30 mg                                                       Polyvinyl alcohol  3 mg                                                       Magnesium stearate                                                                               1 mg                                                       ______________________________________                                    

Pharmaceutical Preparation 2 Powder

A powder having the following composition was prepared according to theconventional method.

    ______________________________________                                               Compound 1                                                                              20 mg                                                               Lactose  300 mg                                                        ______________________________________                                    

Pharmaceutical Preparation 3 Syrup

A syrup having the following composition was prepared according to theconventional method.

    ______________________________________                                        Compound 2               20     mg                                            Refined saccharose       30     mg                                            Ethyl p-hydroxybenzoate  40     mg                                            Propyl p-hydroxybenzoate 10     mg                                            Strawberry flavor        0.1    ml                                            Water to make the total volume                                                                         100    ml                                            ______________________________________                                    

Pharmaceutical Preparation 4 Capsule

Ingredients set forth below were admixed and charged into gelatincapsules in accordance with the conventional method to thereby prepare acapsule.

    ______________________________________                                        Compound 3         20 mg                                                      Lactose           200 mg                                                      Magnesium stearate                                                                               5 mg                                                       ______________________________________                                    

What is claimed is:
 1. Xanthine compounds represented by the followingformula (I): ##STR54## wherein each of X¹ and X² independentlyrepresents oxygen or sulfur; and Q represents: ##STR55## where Yrepresents a single bond or alkylene having 1 to 4 carbon atoms, nrepresents 0 or 1,each of R¹ and R² independently represents hydrogen,lower alkyl, allyl or propargyl, and R³ represents hydrogen or loweralkyl, provided that when Q is ##STR56## then R¹, R² and R³ are notsimultaneously methyl; or a pharmaceutically acceptable salt thereof. 2.The compound according to claim 1, wherein both of R¹ and R² are loweralkyl and R³ is hydrogen; and both of X¹ and X² are oxygen.
 3. Thecompound according to claim 1, wherein each of R¹, R² and R³independently represents hydrogen or lower alkyl.
 4. The compoundaccording to claim 1,wherein each of R¹ and R² independently representsallyl or propargyl and R³ represents hydrogen or lower alkyl.
 5. Thexanthine compound according to claim 4, wherein X¹ and X² are bothoxygen and n is
 0. 6. The compound according to claim 3, wherein Q##STR57##
 7. The compound according to claim 3, wherein Q ##STR58## 8.8-(Noradamantan-3-yl)-1,3-dipropylxanthine or a pharmaceuticallyacceptable salt thereof.
 9. 1,3-Diallyl-8-(3-noradamantyl)xanthine, or apharmaceutically acceptable salt thereof. 10.3-Allyl-8-(3-noradamantyl)-1-propargylxanthine, or a pharmaceuticallyacceptable salt thereof.
 11. A pharmaceutical composition comprising apharmaceutical carrier and, as an active ingredient, an effective amountof a xanthine compound as defined by claim 1 or a pharmaceuticallyacceptable salt thereof.